{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T03:16:47Z","timestamp":1781147807098,"version":"3.54.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates &amp;lt;2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control.<\/jats:p>","DOI":"10.3389\/fped.2023.1168619","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T09:35:46Z","timestamp":1687944946000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia"],"prefix":"10.3389","volume":"11","author":[{"given":"Ronald","family":"Palmen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Sandritter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Malloy-Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Follansbee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1016\/0002-8703(92)90081-6","article-title":"Flecainide acetate for treatment of tachyarrhythmias in children: review of world literature on efficacy, safety, and dosing","volume":"124","author":"Perry","year":"1992","journal-title":"Am Heart J"},{"key":"B2","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.jacep.2021.10.004","article-title":"Arrhythmias in pregnancy","volume":"8","author":"Tamirisa","year":"2022","journal-title":"JACC Clin Electrophysiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1016\/j.jacc.2019.06.024","article-title":"Antenatal therapy for fetal supraventricular tachyarrhythmias: multicenter trial","volume":"74","author":"Miyoshi","year":"2019","journal-title":"J Am Coll Cardiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1016\/j.hrthm.2016.01.029","article-title":"High-dose flecainide is the most effective treatment of fetal supraventricular tachycardia","volume":"13","author":"Strizek","year":"2016","journal-title":"Heart Rhythm"},{"key":"B5","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1080\/14767058.2017.1286317","article-title":"Flecainide as first-line treatment for fetal supraventricular tachycardia","volume":"31","author":"Ekiz","year":"2018","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1136\/hrt.65.1.46","article-title":"Flecainide in the treatment of fetal tachycardias","volume":"65","author":"Allan","year":"1991","journal-title":"Br Heart J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"288","DOI":"10.4103\/apc.APC_31_17","article-title":"Flecainide toxicity in a preterm neonate with permanent junctional reciprocating tachycardia","volume":"10","author":"Karmegaraj","year":"2017","journal-title":"Ann Pediatr Cardiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/j.jemermed.2012.07.050","article-title":"A case of near-fatal flecainide overdose in a neonate successfully treated with sodium bicarbonate","volume":"44","author":"Jang","year":"2013","journal-title":"J Emerg Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1136\/adc.64.6.860","article-title":"Flecainide toxicity","volume":"64","author":"Russell","year":"1989","journal-title":"Arch Dis Child"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e20192608","DOI":"10.1542\/peds.2019-2608","article-title":"Complete heart block secondary to flecainide toxicity: is it time for CYP2D6 genotype testing?","volume":"146","author":"Poh","year":"2020","journal-title":"Pediatrics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/S0379-0738(99)00156-5","article-title":"Fatal flecainide intoxication","volume":"106","author":"Romain","year":"1999","journal-title":"Forensic Sci Int"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1136\/heart.89.10.1261","article-title":"Flecainide induced ventricular fibrillation in a neonate","volume":"89","author":"Ackland","year":"2003","journal-title":"Heart"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1345\/aph.1C487","article-title":"Neonatal flecainide toxicity following supraventricular tachycardia treatment","volume":"37","author":"Hall","year":"2003","journal-title":"Ann Pharmacother"},{"key":"B14","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1517\/17425251003677755","article-title":"Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes","volume":"6","author":"Jeong","year":"2010","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/j.1365-2125.2009.03435.x","article-title":"Effects of CYP2D6 genotypes on age-related change of flecainide metabolism: involvement of CYP1A2-mediated metabolism","volume":"68","author":"Doki","year":"2009","journal-title":"Br J Clin Pharmacol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.ajog.2004.08.030","article-title":"Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy","volume":"192","author":"Tracy","year":"2005","journal-title":"Am J Obstet Gynecol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"989","DOI":"10.2165\/00003088-200544100-00001","article-title":"Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach","volume":"44","author":"Anderson","year":"2005","journal-title":"Clin Pharmacokinet"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1177\/106002809402800907","article-title":"Flecainide distribution, transplacental passage, and accumulation in the amniotic fluid during the third trimester of pregnancy","volume":"28","author":"Bourget","year":"1994","journal-title":"Ann Pharmacother"},{"key":"B19","doi-asserted-by":"publisher","first-page":"45F","DOI":"10.1016\/0002-9149(93)90962-C","article-title":"Pharmacokinetics of amiodarone: implications for drug therapy","volume":"72","author":"Roden","year":"1993","journal-title":"Am J Cardiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"41B","DOI":"10.1016\/0002-9149(84)90501-0","article-title":"Metabolism of flecainide","volume":"53","author":"Conard","year":"1984","journal-title":"Am J Cardiol"},{"key":"B21","first-page":"414","article-title":"Biotransformation and elimination of 14C-flecainide acetate in humans","volume":"12","author":"Mcquinn","year":"1984","journal-title":"Drug Metab Dispos"},{"key":"B22","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1161\/01.CIR.0000109494.05317.58","article-title":"Amiodarone therapy for drug-refractory fetal tachycardia","volume":"109","author":"Strasburger","year":"2004","journal-title":"Circulation"},{"key":"B23","doi-asserted-by":"publisher","first-page":"761","DOI":"10.2165\/11318070-000000000-00000","article-title":"Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II","volume":"48","author":"Zhou","year":"2009","journal-title":"Clin Pharmacokinet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"689","DOI":"10.2165\/11318030-000000000-00000","article-title":"Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I","volume":"48","author":"Zhou","year":"2009","journal-title":"Clin Pharmacokinet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1002\/cpt.1643","article-title":"Pharmvar GeneFocus: cYP2D6","volume":"107","author":"Nofziger","year":"2020","journal-title":"Clin Pharmacol Ther"},{"key":"B26","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1002\/cpt.319","article-title":"Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD","volume":"99","author":"Brown","year":"2016","journal-title":"Clin Pharmacol Ther"},{"key":"B27","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/cts.12895","article-title":"Retrospective review of pharmacogenetic testing at an academic children\u2019s hospital","volume":"14","author":"Roberts","year":"2021","journal-title":"Clin Transl Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1177\/0091270009360533","article-title":"Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science","volume":"50","author":"Leeder","year":"2010","journal-title":"J Clin Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/clpt.2012.130","article-title":"Interpreting pharmacogenetic data in the developing neonate: the challenge of hitting a moving target","volume":"92","author":"Leeder","year":"2012","journal-title":"Clin Pharmacol Ther"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1038\/s41431-021-00920-y","article-title":"Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone)","volume":"30","author":"Matic","year":"2022","journal-title":"Eur J Hum Genet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1002\/cpt.2149","article-title":"Clinical pharmacogenetics implementation consortium guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy","volume":"110","author":"Crews","year":"2021","journal-title":"Clin Pharmacol Ther"},{"key":"B32","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/jbt.20179","article-title":"Ontogeny of human hepatic cytochromes P450","volume":"21","author":"Hines","year":"2007","journal-title":"J Biochem Mol Toxicol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.pharmthera.2008.02.005","article-title":"The ontogeny of drug metabolism enzymes and implications for adverse drug events","volume":"118","author":"Hines","year":"2008","journal-title":"Pharmacol Ther"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1124\/dmd.108.021873","article-title":"Developmental changes in human liver CYP2D6 expression","volume":"36","author":"Stevens","year":"2008","journal-title":"Drug Metab Dispos"},{"key":"B35","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/sj.clpt.6100101","article-title":"Ontogeny of dextromethorphan O- and N-demethylation in the first year of life","volume":"81","author":"Blake","year":"2007","journal-title":"Clin Pharmacol Ther"},{"key":"B36","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1111\/j.1432-1033.1991.tb16411.x","article-title":"Expression of CYP2D6 in developing human liver","volume":"202","author":"Treluyer","year":"1991","journal-title":"Eur J Biochem"},{"key":"B37","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1161\/CIRCULATIONAHA.105.580811","article-title":"Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction","volume":"113","author":"Bezzina","year":"2006","journal-title":"Circulation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1097\/FPC.0b013e328361fb8d","article-title":"SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients","volume":"23","author":"Doki","year":"2013","journal-title":"Pharmacogenet Genomics"},{"key":"B39","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1208\/s12248-014-9592-9","article-title":"Changes in individual drug-independent system parameters during virtual paediatric pharmacokinetic trials: introducing time-varying physiology into a paediatric PBPK model","volume":"16","author":"Abduljalil","year":"2014","journal-title":"AAPS J"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1168619\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T09:35:50Z","timestamp":1687944950000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1168619\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,28]]},"references-count":39,"alternative-id":["10.3389\/fped.2023.1168619"],"URL":"https:\/\/doi.org\/10.3389\/fped.2023.1168619","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,28]]},"article-number":"1168619"}}